Project Summary Allergic disorders have become an issue of major public health significance, especially in children. Although the combined effects of genetic/environmental/developmental may be contributed to the observed global increase of prevalence of allergic disease, the mechanisms underlying modern increases in prevalence of human immune-mediated diseases that likely occur very early in life, such as food allergy remain unclear. Prenatal exposures have been associated with altered risk for allergic disorders. Heritability may pose susceptibility to these conditions. But, genetic mutations with clear relationship to allergy have been elusive. There is an increasing body of epidemiological and animal studies indicating that the immunological environment encountered by the fetus during pregnancy is a strong determinant not only of fetal growth and development, but also of disease risk later in life. However, the mechanisms by which maternal factors regulate the immune function of offspring are not fully understood. Thus, we consider the possibility that food allergy is acquired through maternal imprinting onto the newborn during pregnancy. In this case, if the mother is of an allergic phenotype, the immunologic milieu throughout gestation may be altered which may, in turn, skew the developing fetus toward an allergic phenotype. Our preliminary results showed that feeding a model food antigen to the offspring of mothers who have been sensitized with OVA in the context of the Th2-skewing adjuvant alum prior to pregnancy induced a Th2 type of immune response to this normally tolerogenic stimulus. Moreover, such offspring go on to develop an allergic response when challenged with OVA. These outcomes are antigen specific ? maternal sensitization to bovine serum albumin does not abrogate oral tolerance to OVA in the offspring. They are also dependent on the Th2 environment ? maternal exposure to OVA in the absence of alum does not affect oral tolerance in the offspring. Based on our preliminary results, we hypothesize that intrauterine exposure of maternal Th2-skewed immune response and antigen (OVA) at critical periods of development may contribute to impaired neonatal immune tolerance and predispose the offspring to allergy through (1) utero sensitization to antigen, which may be transferred to the fetal circulation via binding to the neonatal Fc receptor (FcRn), and (2) Th2-dependent transplacental conditioning of the developing immune system in the fetus. Accordingly, these hypotheses will be tested in the experiments described in this revised R21 proposal. The experiments proposed in this application will provide new insights that will be applicable to our understanding of the pathogenesis of food allergy in children. A clearer understanding of the immunoregulatory effects of maternal factors on the fetal and newborn offspring may suggest new therapeutic approaches for the prevention and treatment of food allergy in both children and adults.